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Hi-JAK-ing the ubiquitin system: The design and physicochemical optimisation of JAK PROTACs.
Shah, Rishi R; Redmond, Joanna M; Mihut, Andrei; Menon, Malini; Evans, John P; Murphy, John A; Bartholomew, Michelle A; Coe, Diane M.
Afiliação
  • Shah RR; Medicines Research Centre, GlaxoSmithKline, Stevenage SG1 2NY, United Kingdom; Department of Pure and Applied Chemistry, WestCHEM, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, United Kingdom. Electronic address: Rishi.x.shah@gsk.com.
  • Redmond JM; Medicines Research Centre, GlaxoSmithKline, Stevenage SG1 2NY, United Kingdom.
  • Mihut A; Medicines Research Centre, GlaxoSmithKline, Stevenage SG1 2NY, United Kingdom.
  • Menon M; Medicines Research Centre, GlaxoSmithKline, Stevenage SG1 2NY, United Kingdom.
  • Evans JP; Medicines Research Centre, GlaxoSmithKline, Stevenage SG1 2NY, United Kingdom.
  • Murphy JA; Department of Pure and Applied Chemistry, WestCHEM, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, United Kingdom.
  • Bartholomew MA; Medicines Research Centre, GlaxoSmithKline, Stevenage SG1 2NY, United Kingdom.
  • Coe DM; Medicines Research Centre, GlaxoSmithKline, Stevenage SG1 2NY, United Kingdom.
Bioorg Med Chem ; 28(5): 115326, 2020 03 01.
Article em En | MEDLINE | ID: mdl-32001089
PROTACs have recently emerged as a novel paradigm in drug discovery. They can hijack existing biological machinery to selectively degrade proteins of interest, in a catalytic fashion. Here we describe the design, optimisation and biological activity of a set of novel PROTACs targeting the Janus kinase family (JAK1, JAK2, JAK3 and TYK2) of proximal membrane-bound proteins. The JAK family proteins display membrane localisation by virtue of their association with cytoplasmic tails of cytokine receptors, and there are no reports of a successful PROTAC strategy being deployed against this class of proteins. JAK PROTACs from two distinct JAK chemotypes were designed, optimising the physicochemical properties for each template to enhance cell permeation. These PROTACs are capable of inducing JAK1 and JAK2 degradation, demonstrating an extension of the PROTAC methodology to an unprecedented class of protein targets. A number of known ligase binders were explored, and it was found that PROTACs bearing an inhibitor of apoptosis protein (IAP) ligand induced significantly more JAK degradation over Von Hippel-Lindau (VHL) and Cereblon (CRBN) PROTACs. In addition, the mechanism of action of the JAK PROTACs was elucidated, and it was confirmed that JAK degradation was both IAP- and proteasome-dependent.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pirimidinas / Quinoxalinas / Ubiquitina / Fatores de Transcrição STAT / Janus Quinases / Proteólise Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pirimidinas / Quinoxalinas / Ubiquitina / Fatores de Transcrição STAT / Janus Quinases / Proteólise Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2020 Tipo de documento: Article